Novel antibody drug constructs can be designed and implemented to treat malignant glioblastoma multiforme (GBM). GBM is a malignant astrocytoma and one of the most common glial tumors. GBM is a rapidly fatal and incurable cancer, for which novel therapeutic approaches are needed. The standard-of-care for newly diagnosed GBM is a three-pronged regimen to treat the disease: (i) surgical resection to remove the tumor, (ii) whole-brain or stereotactic external-beam radiotherapy to treat residual disease, and (iii) chemotherapy, again to address residual disease. However, despite increasingly more sophisticated technology, all three of these modalities have limitations regarding untoward damage from excision and radio-toxicity affecting healthy brain tissue and the probability of recurrence is nearly universal. The approach described in this application may potentially afford clinical methods to specifically target the angiogenic and aberrant vascular endothelium in GBM; locally irradiate those vessels and the adjacent perivascular cancer stem cell niche with cytotoxic alpha particles; and favorably remodel the vascular endothelium and improve subsequent chemotherapy. Furthermore, this agent will be administered intravenously and rapidly access the tumor vasculature, but it does not have to transit the Blood Brain Barrier to be effective. Such an agent could potently eradicate tumor while sparing normal tissue and could impact the way malignant astrocytomas are treated. The significance of the application of this agent against GBM entails filling the medical and scientific gap in the current treatment regimen by using a targeting radio-therapeutic construct to specifically treat this disease in an animal model of GBM. The proposed agent is designed to (i) target the GBM vascular network and bind to the monomeric form of vascular endothelium-cadherin (VE-cadhm), an epitope expressed on the tumor vessel endothelial cell surface, employing an alpha-particle emitting antibody construct; (ii) deliver a cytotoxic dose of short-ranged, high energy alpha-particle emissions to these VE-cadhm-expressing cells and also to their local microenvironment via the decay of the 225Ac radionuclide; and (iii) favorably remodel the GBM VE to improve subsequent chemotherapy. Biodistribution studies will be employed to determine the amount of agent delivered, its residence time and precise location within the GBM. These biodistribution data will also be analyzed to calculate dosimetric values. Combined schedule-dependent therapy studies will be undertaken to investigate efficacy. Mechanistic studies will be performed using established methods to determine the morphological, maturational, and permeability changes in the GBM VE as a consequence of the alpha- therapeutic component. We have an established track record of effectively translating other targeted alpha- particle emitting antibody constructs (anti-CD33) from the bench to the clinic to treat leukemia. The data generated by the preclinical study of this proposed vascular targeting agent will be used to support the application for clinica use in patients with GBM at MSKCC